Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) related, progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from POAG is a condition of public health significance worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of POAG allowing for implementation of effective screening and prevention strategies and development of novel therapies. POAG has significant heritability and recent genome-wide association studies, including our NEIGHBORHOOD GWAS, have identified 30 POAG loci defined by common genomic variants. However, in addition to common variants the complex POAG genetic architecture is likely to also include contributions from rare coding variants as has been discovered for other complex traits. Large-scale studies of rare coding variation and glaucoma have not yet been done. Of the current POAG loci, the majority appear to contribute to disease through elevation of IOP. However, approximately one third of U.S. glaucoma cases are ?normal? tension (NTG), charaterized by progressive optic nerve degeneration despite normal IOP. Our prior NTG GWAS identified two loci: 8q22, a loci not found in POAG GWASs and CDKN2BAS, a locus known to effect ganglion cell vulnerability. There results suggest that genes associated with NTG can influence susceptiblity to optic nerve degeneration, and that identification of these optic-nerve-related loci is more likely using NTG cases and controls for GWAS, rather than POAG overall. For the next funding period we propose the following specific aims: 1) complete a larger-scale well-powered NTG GWAS to discover novel loci; 2) assess contributions of rare coding variants to NTG and high-tension POAG (HTG) using whole exome sequencing; 3) explore potential protective effects of dietary factors and medications on cases with high-risk variants in POAG loci related to lipid metabolism and to mitochondrial function; and 4) support additional clinical data collection for the NEIGHBORHOOD.